The central theme of this Program Project is the development and characterization of new mouse models of human disease. Development of a such models requires a wide range of expertise. By bringing together a diversity of scientific expertise in mouse model development, this Program Project insures the multidisciplinary interactions necessary not only for successful model development, but also for comparison to similar disease states in other domestic animals and in humans. Four disease models to be analyzed are controlled by genes mapping to Chromosome 8 of the mouse. These include a mutant gene producing a model for human polycystic kidney disease, a gene controlling susceptibility to diet-induced cholelithiasis (gallstones), a mutant characterized by an adrenal cortex developmental anomaly, and an obesity mutation conferring susceptibility to type 2 diabetes. Two interactive projects are designed to develop and characterize new mouse models for non-insulin dependent diabetes mellitus that more accurately resemble the disease in humans. A mouse autosomal recessive mutation similar to human harlequin ichthyosis will also be characterized at the genetic and pathophysiolgic levels. A GENE MAPPING CORE will provide special synergism to the three projects with specific aims focused on fine resolution mapping of disease-producing mutations on Chromosome 8. This CORE will greatly expedite the collaborative development of a fine structure map of the relevant regions on Chromosome 8 at a resolution of 0.1 cM. This CORE will also provide essential genetic information related to the aims of the other three projects. A PATHOLOGY CORE will also bring multidisciplinary expertise into the evaluation of the mouse models and their relation to human disease. By utilizing the expertise of outside collaborators, the PATHOLOGY CORE will allow the Program Project investigators to bridge the gap between disease processes in mice and humans. An ADMINISTRATIVE CORE will facilitate the flow of genetic, pathophysiologic, and histopathologic information among the Program Project participants.